The present invention relates to an arrangement and to a method for producing high-purity crystals such as temperature-sensitive pharmaceutical agents, in a countercurrent crystallization process.
Arrangements of the type of the invention are provided with crystallizers operated in a column-like manner in countercurrent principle so that for substances contained in mother liquors a separation effect is produced that allows the purification of said substances.
The purification of substances by crystallization has been known for many years. Up to now, the purification of substances, particularly of pharmaceutical agents, is still one of the most effective purification methods. If a very high degree of final purities (>99.99%) is required, the conventional crystallization rapidly comes to its limits. In practice, a complex impurity profile with 5 to 10 by-products is often obtained. The by-products can be principally depleted in the target product by crystallization but they have very different depletion properties. A high final purity cannot be reached in one crystallization stage but in a crystallization method that consists of several stages and fractions. The purity is inversely proportional to the yield obtained. Therefore, the required time increases and the yield losses even grow exponentially with the number of stages. For example, after a fivefold recrystallization the total yield is only 17% to 70% per stage. The major part of the substance is contained in mother liquors. A complex fractionation process is the only way to bring a portion of it to the desired degree of final purity.
In the field of distillation and extraction a continuous fractionation and unification of the phases in countercurrent principle makes it possible to multiply the fractioning effects based on the distribution equilibration and thus to develop very efficient fractionation processes. In practice, rectification or extraction columns or Mixer-Settler-systems are used as equipment for these processes.
Principally, such an idea can also be transferred to crystallization because also here the fractioning effect (purification effect) is based on the different distribution of the individual impurities between the crystallization product and mother liquid phases. However, the technological implementation of the multiplicative fractionation effect analogous to extraction/rectification is difficult because the phase transitions are solid-liquid-transfers.
There is a number of publications about the classical process management in column-like equipments (DE 32 39 244 A1, EP 0242 18 A1, U.S. Pat. No. 3,154,395, U.S. Pat. No. 4,279,130). These processes are complex and susceptible to faults; the apparatus belonging to them are complicated and tailored to the relevant crystallization problem. Frequently they have only low bottom efficiency due to difficult substance transfer conditions (G. Matz, “Fraktionierte Kristallisation” (Fractionated crystallization), Chemie-Ingenieur-Technik, 52, (1980), no. 7, p. 562-570). Unlike rectification or extraction columns they could not be established as standard methods in industrial practice.
The alternative to the classical continuous process management in column-like arrangements is a multi-stage process in separated, technologically similar crystallization units. It can also be performed as a more or less continuous procedure.
A number of procedures and systems for the fractionated, multi-stage crystallization is known (see, for example, U.S. Pat. No. 4,787,985, U.S. Pat. No. 5,127,921). According to these disclosures the yield losses in multiple crystallizations are reduced by a countercurrent flow of mother liquor and crystallization product. Moreover, the purification effect per stage can be increased by a partial reflow of the crystallization product and mother liquor in each stage. But this will of course reduce the throughput.
Disadvantages of the methods and arrangements known so far are the complex equipment and procedures required. A large number of basic process operations that can be separately performed with individual apparatus are connected with each other in quantity flow according to prior art.
In U.S. Pat. No. 5,127,921, for example, a crystallizer, a dissolution vessel, an external solid-liquid-separation unit and diverse buffer vessels for mother liquor and crystallization product are required for each crystallization stage. Moreover, pumps for the transport of the solution and systems for the reflux separation are required and distillation recipients must be additionally provided for the possible evaporation of the solution.
This lack of technological compactness inevitably leads to a complex connection of the sections of the arrangement and, in the event of a high stage number, to a complicated equipment layout. Consequently, the automation for maintaining a stationary countercurrent regime and the control for synchronizing all stages are also very problematic, particularly as external solid-liquid separators (centrifuges, filters, etc.) and solid substance transports between separators and dissolution vessels are required that can be very complex in view of the texture of the crystalline material (grain size).
The separation of the equipment of the dissolution process and of crystallization is disadvantageous, too, because hardly solvable crusts can be produced on the cooling surfaces of the crystallizer. According to this procedure, the crystallization is achieved by cooling a solution that is as saturated as possible. Therefore, the yield is mainly determined by the temperature gradient of the solubility. From an economic point of view, this means that the yield scope is considerably restricted despite the countercurrent principle. A lot of substances, particularly pharmaceutical agents, do not have a sufficient solubility gradient to obtain economic yields with reasonable energetic efforts.
An additional evaporation could be possible, although not described, but it requires further equipment as well as technological and logistic efforts in addition to the already expensive technical apparatus.
U.S. Pat. No. 4,787,985 also discloses a countercurrent crystallization process for purifying chemical substances by means of a plurality of repeating, identical technological stages. But also here, several basic technical operations with separated equipment are connected per stage: crystallizer, recrystallizer, filter system, separator, thickening unit and/or wash columns and pumps. A completely continuous process is described that, as in the other examples, is only suitable for crystallizations from the melt and not from solvents.
U.S. Pat. No. 5,505,924 also describes a multi-stage countercurrent flow process with the appropriate equipment. Within the u-shaped crystallization units heating and cooling zones are arranged for the locally separated dissolution and recrystallization processes. The transport to the next crystallization unit is realized in form of a solid via perforated containers that absorb the crystallization product. The mother liquor is separated by dripping it off or washing after its removal from the cooling zone. Then, these crystallization containers are brought into the heating zone of the next crystallization unit via an automated transport technology system for being dissolved. This open transport technology is only suitable for aqueous solutions. Moreover, the transfer of the crystallization product is not complete. Also here, the described procedure can only be applied if the solubility has a sufficiently high temperature dependency. The yield exclusively depends on the temperature difference between the heating and the cooling zone. As already mentioned above, in many cases this is not sufficient for obtaining economic yields.
A further disadvantage of the described published procedures is the transport of the required heat via cooling areas to maintain the supersaturation condition of the solution during the crystallization. During longer process periods this method can cause hardly solvable deposits that can have a negative influence on the stability in the stationary operation.
The methods and arrangements of the state of the art are not suitable for crystallization products that do not crystallize in suspension but tend to deposit on apparatus surfaces.
Depending on the crystallization properties, fine grain particles can additionally impede an external filtration and washing.
Further process technologies and apparatus for multi-stage fractionated crystallizations have been developed so far, particularly in the field of melt crystallization (for example, see EP 0891 798 A1 and G. Wellinghoff, K. Wintermantel: “Schmelzkristallisation theoretische Voraussetzungen and technische Grenzen” (Melt crystallization theoretical conditions and technical limits), Chemie-Ingenieur-Technik no. 9, p. 881-891). These methods are mainly based on the formation of crystal layers on metal surfaces thus allowing a technologically simple separation of the mother liquor and crystallization product. But due to the thermal sensitivity of many pharmaceutical agents at the melting point these processes are normally not suitable for their purification.
DE 602 07 852 A1 discloses a crystallization method in which several crystallizers are simultaneously operated in a continuous manner (not batch by batch) in co-current (not countercurrent). In the crystallization stages, different evaporation rates of a suspension are achieved and a complete dissolution and crystallization do not happen per stage as it is normal for the multi-stage, fractionated crystallization. From the point of purification crystallization it is a one-stage process. The evaporation heat is provided by a gradual expansion and thus cooling of the suspension from overpressure to the normal pressure level. Distillate can be led back for dilution and thus for controlling the purification.
In the procedure according to DE 602 07 852 A1 the recovery of crystalline terephthalic acid, which contains less than 150 parts per million on weight (ppmw) of p-toluic acid referred to the weight of the terephthalic acid, is performed in four steps:
In the first step, a solution of terephthalic acid and p-toluic acid are subject to a temperature ranging from 260 to 320° C. and a defined pressure that is sufficiently high to keep the solvent in the liquid phase.
In the second step the solution of the first step is supplied to a crystallization zone that comprises a plurality of series-connected crystallizers in which the solution is subject to a speed-determined evaporation cooling by the sequential reduction of pressure and temperature to achieve the crystallization of terephthalic acid. At the end of the crystallization zone the pressure of the solution corresponds to ambient pressure or less.
In the third step the solvents evaporated from the crystallizers condense and the condensed solvent is led back into the crystallization zone at a point that follows the crystallizer from which it was obtained.
In the fourth and last step of the process solid, crystalline terephthalic acid is obtained by the liquid-solid-liquid separation at ambient pressure.